We extract new parton distribution functions (PDFs) of the proton by global analysis of hard scattering data in the general-mass framework of perturbative quantum chromodynamics. Our analysis includes new theoretical developments together with the most recent collider data from deep-inelastic scattering, vector boson production, and single-inclusive jet production. Due to the difficulty in fitting both the DO Run-II W lepton asymmetry data and some fixed-target DIS data, we present two families of PDFs, CT10 and CT10W, without and with these high-luminosity W lepton asymmetry data included in the global analysis. With both sets of PDFs, we study theoretical predictions and uncertainties for a diverse selection of processes at the Fermilab Tevatron and the CERN Large Hadron Collider.